Methods of treating skin conditions using cyclolignan compounds

ABSTRACT

The present invention includes compositions and methods for the treatment of skin conditions by administration of a cyclolignan such as picropodophyllin and/or a derivative, metabolite, analog, prodrug, pharmaceutically acceptable salt, or hydrate thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national phase application filed under 35U.S.C. §371 of International Application No.: PCT/US2014/037523, whichwas filed May 9, 2014, and which claims the benefit of the filing dateof U.S. Provisional Application No. 61/822,072, which was filed on May10, 2013. For the purpose of any U.S. application that may claim thebenefit of U.S. Provisional Application No. 61/822,072, the contents ofthat earlier filed application are hereby incorporated by reference intheir entirety.

FIELD OF THE INVENTION

The present invention is directed to methods of treating various skinconditions by administering to a patient a composition that includes acyclolignan compound such as picropodophyllin, either alone or incombination with one or more additional active ingredients.

BACKGROUND OF THE INVENTION

Hyperproliferative skin diseases are a common dermatologic problem andinclude both benign and malignant skin conditions. Benignhyperproliferative skin conditions include such entities as common warts(verruca vulgaris), flat warts (verruca plana), seborrheic keratosis,actinic keratosis, psoriasis, certain types of ichthyosis, genital warts(condyloma accuminatum), molluscum contagiosum, and acanthosisnigricans. Malignant hyperproliferative skin conditions include suchentities as basal cell carcima, squamous cell carinoma, squamous cellcarcinoma in situ (Bowen's disease), melanoma, and sarcoma.

Various treatments for hyperproliferative skin conditions includingphysical destructive modalities and pharmacologic treatment. Commonlyused physical destructive techniques include cryotherapy,electrosurgery, laser surgery, dermabrasion, and chemical ablation.Commonly used phamacologic treatments for hyperproliferative skinconditions include topical fluouracil, imiquimod, alpha and beta hydroxyacids, cantharidin, corticosteroids, ingenol menbutate, and tretinoin.While these topical pharmacologic treatments are at times effective,many are limited by the adverse side-effect profile including extremeirritation (ingenol mebutate and fluorouracil), modest efficacy(imiquimod), and systemic toxicity (cantharidin). Because of theselimitations with existing topical treatments for hyperproliferative skinconditions, physicians for years have sought to develop alternativepharamcologic treatments with enhanced efficacy and decreasedside-effects.

SUMMARY OF THE INVENTION

The present invention provides compositions that includepicropodophyllin (or a derivative thereof, as described further herein)and methods of using these compositions in the treatment of various skinconditions. The methods include administering, to a patient, acomposition (e.g., a pharmaceutical composition) comprisingpicropodophyllin and/or any one or more of a pharmacologicallyacceptable precursor, prodrug, or other derivative thereof. In lieu of amethod of treatment, the invention can be described as the use of thepresent compositions in the preparation of a medicament (e.g., in thepreparation of a medicament for the treatment of a condition describedherein).

Picropodophyllin derivatives useful in the methods of the inventioninclude isomers, epimers, salts, esters and analogs, that have forexample, ring modifications or ring substitutions as described furtherbelow. Also included are hydrates, polymorphs, glycosides and prodrugs,as well as related compounds such as etoposide, teniposide,demethoxyepiisopicropodophyllin, tafluposide, etopophos, NK611 and theirderivatives. The derivatives useful in the methods and uses of thecurrent invention are described, for example, by Vitale et al., (Journalof Organic Chemistry, 73:5795-5805, 2008; Nagar et al., Pharmacophore2(2):124-134, 2011; U.S. Pat. Nos. 5,739,114; 7,629,381, 7,662,851;7,709,526; 8,158,809; and 8,389,747; United States Patent ApplicationNos. US20050009759 and US20100216728; and International PatentApplication Publication Nos. WO/2013132262 and WO/2013132263. Thecontent of these references is incorporated herein by reference in itsentirety.

Picropodophyllin derivatives useful in the methods of the invention maybe prepared from podophyllin or podophyllotoxin using methods known toone of ordinary skill in the art (for example, see Stadler and Bach,Angew. Chem, Int. Ed. Engl., 47(39):7557, 2008); Berkowitz et al. J.Org. Chem. 65:847-860, 2000; United States Patent Application Nos.US20090271879 and US20130245285 (which are incorporated herein byreference in their entirety); and Vitale et al. Journal of OrganicChemistry, 73:5795-5805, 2008).

In one embodiment, the methods include administering a pharmaceutical orphysiologically acceptable composition that includes a therapeuticallyeffective amount of picropodophyllin and/or one or more of itspharmaceutically acceptable derivatives. Such a composition and othersdescribed herein can be administered to treat one or more of thefollowing skin or medical conditions: verruca (warts), actinickeratosis, condyloma, molluscum contagiosum, squamous cell carcinoma,basal cell carcinoma, squamous cell carcinoma in situ, melanoma,acanthosis nigricans, porokeratosis, seborrheic keratosis,fibroepithelial polyp (skin tag), melasma, angiosarcoma, Kaposi'ssarcoma, sarcoma, acne (e.g., vulgaris, comedonal acne vulgaris, orcystic acne vulgaris) and conditions related thereto (e.g., scarring),perioral dermatitis, trichoepithelliomas and related genetic syndromesthat cause multiple trichoepitheliomas and dermatofibrosarcomaprotuberans in a patient.

In another aspect, the invention features pharmaceutical compositionsthat include (a) picropodophyllin, another compound described herein,and/or a pharmaceutically acceptable derivative thereof (in, forexample, therapeutically effective amounts), and (b) a secondanti-neoplastic agent (e.g., fluorouracil, imiquimod, or ingenolmebutate) (in, for example, a therapeutically effective amount). Thecompositions can be formulated as described herein. For example, theycan be formulated for topical application and may include propyleneglycol.

DETAILED DESCRIPTION

The methods of the invention can be carried out by administering to apatient a compound of Formula I or a pharmaceutically acceptablederivative thereof:

Picropodophyllin is a member of the class cyclolignan family ofcompounds. It contains a fused cyclic ring system and four adjacentchiral centers. In Formula I, each R₁ can be the same or different andcan be OH or OCH₃, where n is 0, 1 or 2. R₂, R₃ and R₄, which can be thesame or different, are, independently, H, OH, O, OOCH₃, OOCH₂CH₃, OCH₃,or OC₂H₅, and R₃ and R₄ together are an ether or a lactone, which mayoptionally contain a double bond Δ⁷⁽⁸⁾ or Δ^(8(8′)). The compound ofFormula I can also be used for the preparation of a medicament or forthe preparation of a medicament for the treatment of a condition asdescribed herein.

The carbons at positions 9 and 9′ of the compounds of Formula I have acis configuration, i.e. the 8-9 and 8′-9′ bonds are located in or abovethe plane of the carbon ring (beta bonds), as indicated by the solidlines in the Formula I. A wavy line, as between the carbons 1′ and 7′,indicates that the bond can be either an alpha or a beta bond. An alphabond, that is below the plane of the carbon ring, is illustrated by adashed line. The benzene ring should preferably be in α-position, as isdemonstrated by picropodophyllin, deoxypicropodophyllin,α-apopicropodophyllin, and β-apopicropodophyllin.

Picropodophyllin Derivatives Useful in the Methods of the Invention

Picropodophyllin derivatives suitable for use in the invention includebut are not limited to hydrates, polymorphs, glycosides, prodrugs,isomers, epimers, salts, esters and analogs, that have for example, ringmodifications or ring substitutions. Non-limiting examples ofsubstitutions include methylation, hydroxylation, hydroxymethylation,trifluoromethoxylation, methoxylation and halogenation. The derivativesinclude but are not limited to 3′-demethoxy-picropodophyllin,4′-demethoxy-picropodophyllin, 5′-demethoxy-picropodophyllin,3′,4′-didemethoxy-picropodophyllin, 3′,5′-didemethoxy-picropodophyllin,4,5′-didemethoxy-picropodophyllin,3′,4′,5′-tridemethoxy-picropodophyllin, deoxypicropodophyllin,epipicropodophyllin, 4β-azidopicropodophyllin, α-apopicropodophyllin,β-apopicropodophyllin, α-peltatin, β-peltatin,demethoxyepiisopicropodophyllin, etoposide, teniposide, tafluposide,etopophos, NK611, GL-331, NPF, TOP-53 and their derivatives. Some ofthese derivatives are described by Vitale et al. (Journal of OrganicChemistry 73:5795-5805, 2008; Nagar et al., Pharmacophore 2(2):124-134,2011; U.S. Pat. Nos. 5,739,114; 7,629,381; 7,709,526; 8,158,809;8,389,747; United States Patent Application Publication Nos.0520050009759, US20090271879; US20100216728; and International PatentApplication Publication Nos. WO 2013132262, WO 2013132263. The contentof the U.S. patents and published patent applications are incorporatedherein by reference.

Vitale et al. (Journal of Organic Chemistry, 73:5795-5805, 2008)describe vinyl-lactones and aryltetralin lignan derivatives derivativesthat are useful in the present methods. Axelson and Bremberg (WO2013/132262 and WO 2013/132263) have described analogs ofpicropodophylin useful in the methods of the current invention. Theseanalogs can be defined by the following structure:

wherein

R₁ is OH, H, D or —O—C(O)—C₁-C₆ alkyl;

R₂ is H or D

R₃ and R₄ is each and independently H or D

R₅, R₆ and R₇ is each and independently H or D

Exemplary picropodophyllin analogs described by Axelson and Bremberguseful in the methods of the current invention include but are notlimited to:

-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    acetate;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    propanoate;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    pentanoate;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    heptanoate;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    undecanoate;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    palmitate;-   3-oxo-3-(((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl)oxy)propanoic    acid;-   9-oxo-9-(((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl)oxy)nonanoic    acid;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)acetate;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    2-aminoacetate;-   (R)-(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methyl butanoate;-   (R)-(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    2-amino-3-methylbutanoate;-   (R)-(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-methylpentanoate;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    (28)-2-amino-4-methylpentanoate;-   (2R,3S)-(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    2-((((9H-fluoren-9-yl)methoxy) carbonyl)amino)-3-methylpentanoate;-   (2R,3S)-(5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl-2-amino-3-methyl    pentanoate;-   Methyl    ((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl)    carbonate;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    dimethylcarbamate;-   bis((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl)    nonanedioate;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    4-methylbenzoate;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    3-(4-methoxyphenyl)propanoate;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    isoxazole-5-carboxylate;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    2-(2,5-difluorophenyl)acetate;-   (SR,SaR,BaS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,Sa,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    2-((tertbutoxycarbonyl)amino)propanoate;-   Methyl    ((5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl)    fumarate;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    2-(3-bromophenyl)acetate;-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    2-(4-methylphenylsulfonamido)acetate; and-   (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl    2,2-dimethyl-5-oxotetrahydrofuran-3-carboxylate.

Berkowitz et al. (U.S. Patent Application Publication No. 20090271879)describe yet other analogs useful in the methods of the currentinvention. These analogs are defined by the formula:

wherein X, X′, Y, Y′ and Z may be independently hydrogen; deuterium;tritium; a C₁-C₈ saturated or unsaturated, alkyl or cycloalkyl group; ahydroxyl group; an ether-protected hydroxyl group bearing a C₁-C₈saturated or unsaturated alkyl or cyclic alkyl group; a carboxylateester-protected hydroxyl group derived from a C₁-C₈ saturated orunsaturated, cyclic or acyclic, carboxylic acid; a hydroxyl groupprotected as a phosphate mono-, di- or triester, the di-, or triesterhaving C₁-C₄ saturated or unsaturated alkyl group(s); a C₁-C₈ alkoxy, aC₁-C₄ alkoxy; a phosphonate mono- or diester-protected hydroxyl groupderived from a C₁-C₈ saturated or unsaturated, cyclic or acyclic,phosphonic acid wherein the diester also contains a C₁-C₈ saturated orunsaturated alkyl group; a phosphinate ester-protected hydroxyl groupderived from a phosphinic acid bearing two C₁-C₈ saturated orunsaturated, cyclic or acyclic, alkyl groups; a hydroxyl group protectedas a sulfate mono- or diester bearing a C₁-C₄ saturated or unsaturatedalkyl group; a hydroxyl group protected as a sulfonate ester derivedfrom a sulfonic acid bearing a C₁-C₈ saturated or unsaturated, cyclic oracyclic, alkyl group; an amino group; a primary or secondary aminebearing 1 to 2 C₁-C₈ saturated or unsaturated alkyl group(s),respectively; a carboxamide-protected, unsubstituted or primary aminebearing a C₁-C₄ saturated or unsaturated alkyl group; an amino groupderived from a C₁-C₈ saturated or unsaturated, cyclic or acyclic,carboxylic acid; a carboxylic acid; a carboxylate ester bearing a C₁-C₄saturated or unsaturated alkyl group; a phosphonic acid; aphosphonatemono- or diester bearing 1 to 2 C₁-C₄ saturated orunsaturated alkyl group(s), respectively; a phosphinic acid having aC₁-C₈ saturated or unsaturated, cyclic or acyclic, alkyl group or esterbearing a C₁-C₄ saturated or unsaturated alkyl group; a formyl group; anacetyl group; a benzoyl group; a carboxamide group derived from ammoniaor from a primary or secondary amine bearing 1 to 2 C₁-C₄ saturated orunsaturated alkyl group(s), respectively; a sulfhydryl group; athioether bearing a C₁-C₈ saturated or unsaturated, cyclic or acyclic,alkyl group; a sulfonic acid, a sulfonate ester bearing a C₁-C₄saturated or unsaturated alkyl group; an alkylsulfonyl group bearing aC₁-C₈ saturated or unsaturated, cyclic or acyclic, alkyl group; aphenylsulfonyl group; a sulfoxide bearing a C₁-C₈ saturated orunsaturated, cyclic or acyclic, alkyl group; a phenylsulfoxide; aphenylseleno group; a phenylselenoxide; an azide; a halogen; a cyanogroup; a nitro group; a nitroso group; a diazonium group; or atrifluoromethyl group with the proviso that when X and X′ are H, Y, Y′,and Z cannot all be methoxy. The preferred derivatives, described in US20090271879, that are useful in the methods of the current inventionare:

Synthesis of Picropodophyllin and Derivatives Useful in the Methods ofthe Invention

Picropodophyllin may also be precipitated by decomposing podophyllin inan alkali or generated by microbes using methods known to one ofordinary skill in the art (for example, see Stadler and Bach, Angew.Chem, Int. Ed. Engl., 47(39):7557, 2008). For example, Penicilliumstrains can isomerize podophyllotoxin to picropodophyllin (Guo et al.,J. Asian Nat. Prod. Res. 1(2):99-102, 1998). Other methods for synthesisof picropodophyllin suitable for current invention include but are notlimited to enzyme-assisted asymmetric total synthesis of(−)-picropodophyllin, reviewed by Berkowitz et al. (J. Org. Chem.65:847-860, 2000); United States Patent Application Nos. US20090271879and US 20130245285; Vitale et al., (Journal of Organic Chemistry,73:5795-5805, 2008).

Berkowitz et al., (J. Org. Chem. 65:847-860, 2000) describeenzyme-assisted asymmetric total synthesis of (−)-picropodophyllin thatfeatures achievement of asymmetry using stereospecificity of enzymes tocatalyze desymmetrization of advanced meso diacetate intermediate. Theprecursor used in this method is piperonal, which is converted viabromination, acetalization, and halogen-metalexchange/hydroxymethylation to an isobenzofuran intermediate (IBF).Treatment of this intermediate with HOAc with pure dimethyl maleateresults in a 2.8:1 endo:exo mixture of maleate IBF Diels-Alder adducts.Alternatively, the desired endo meso diester is obtained using dimethylacetylene dicarboxylate as the dienophile, followed by catalytichydrogenation. Reduction of the desired endo meso diester using LiAlH₄leads to formation of a meso diol intermediate, which is then convertedto the corresponding meso diesters by treatment with Ac₂O, BzCl, andPhCH₂COCl. A suitable acyl transfer enzymes is then used in the nextstep to introduce asymmetry, yielding a key chiral intermediate. Use ofa specific protecting groups and Swern oxidation leads to an aldehydeintermediate, which produces dihydronaphthalene intemediates havingproperly set C3 and C4 stereocenters using retro-Michael ring opening;which is then subjected to conjugate addition using a arylcopper reagentderived from (3,4,5-trimethoxy)phenylmagnesium bromide and CuCN. Theconjugate is then subjected to lactonization and SEM deprotection toyield (−)-picropodophyllin.

Another method of synthesis of picropodophyllin useful in the methods ofthe current invention is described by Axelsson et al. (United StatesPatent Application No. US 20130245285). This method is based on thefollowing epimerization reaction using Heck reaction conditions:

followed by cyclization in the presence of a base; a protic solvent or amixture of a protic and an aprotic solvent; and a transition metalcomponent one-pot reaction; wherein,

P is an activating group;

R may be the same or different, is OH, OCH₃, OCH₂CH₃, F, Cl, CH₃ or CF₃;and

n is 0, 1, 2, 3, or 4.

Vitale et al. (Journal of Organic Chemistry, 73:5795-5805, 2008)describe synthesis of certain picropodophyllin analogs useful in themethods of the current invention. These analogs are synthesized byPd-catalyzed intramolecular allylic alkylation of unsaturated malonylesters to give 4-vinylsubstituted γ-lactones, only with a substrateincorporating a suitably positioned silicon moiety. This intermediate isfurther subjected to ionization toward the desired η3-allylpalladiumcomplex resulting 4-[dimethyl-(2-thienyl)silylvinyl]lactone; which issubsequently engaged into Hiyama couplings with various iodoarenes, togive the corresponding 4-(R-styryl)-γ-lactones. Specifically substitutediodoarene is used to generate advanced tetracyclic lactone intermediatederivatives of lignans belonging to the podophyllotoxin family, whichare then converted to picropodophyllin analogs by electrophilic aromaticsubstitution with a variety of electron-rich arenes.

The invention especially refers to the use of compounds of Formula II ora pharmaceutically or physiologically acceptable derivative thereof:

In Formula II, R₂ can be H, OH, O, OOCH₃, OOCH₂CH₃, OCH₃, or OC₂H₅.Formulas I and II encompass picropodophyllin, which is known to haveactive medicinal properties. It is naturally found in small amounts inthe rhizome or stem of the perennial herb plant American Mayapple(Podophyllum peltatum), commonly referred to by many other names, suchas Indian apple, and Podophyllum emodi, also called Podophyllumhexandrum, Himalyan mayapple or Indian may apple. The compounds can begenerated by synthetic methods known in the art.

Methods of the Invention

Podophyllin is a resin that may be extracted from the rhizome and rootsof the same herb plants described above, and both podophyllin andpicropodophyllin are cyclolignans (phytoestrogens characterized by apair of propylbenzene groupings) having an additional ring structure.Podophyllin is well known for its ability to remove genital warts. Italso has anti-cancer activities, but its use is somewhat limited becauseof its toxicity profile. A purified form, podofilox (tradenames:Condylox and Wartec solution) is currently available for the treatmentof warts.

Picropodophyllin has more recently been shown, in WO 02/102804, to be anpotent inhibitor of the insulin-like growth factor-1 (IGF-1). IGF-1 is ahormone that binds to the insulin-like growth factor 1 receptor (IGF1R)and the insulin receptor with a higher affinity for the former. IGF1R isa tyrosine kinase receptor and activates the AKT signaling pathway aswell as other signaling pathways. Activation of IGF is important inmediating cell growth and proliferation. It is also an inhibitor ofapoptosis. IGF-1, in large part, mediates the effects of growth hormone,promoting growth in almost every cell in the body.

As noted, the methods of the invention can include the administration ofa pharmaceutically acceptable salt of a compound described herein. Forexample, the salt can be an acid-addition salt (e.g., a salt formed withan inorganic acid), an alkali metal salt (e.g., an alkaline earth metalsalt), or a salt formed with an organic base. Useful salts includeacetate, fumarate, maleate, tartrate, citrate, hydrochloride,hydrobromide, sulphate and phosphate salts. Hydrates of picropodophyllininclude podophyllic acid.

In some aspects the current invention include method of treatment ofskin diseases or skin conditions comprising administration of acomposition comprising picropodophyllin, another compound describedherein, and/or a pharmaceutically acceptable precursor orprodrugprecursor or prodrug thereof, wherein the skin condition isverruca (warts), common warts (verruca vulgaris), flat warts (verrucaplana), genital warts (condyloma accuminatum), certain types ofichthyosis, psoriasis, actinic keratosis, condyloma, molluscumcontagiosum, acanthosis nigricans, porokeratosis, seborrheic keratosis,fibroepithelial polyp (skin tag), melasma, and malignanthyperproliferative skin conditions including angiosarcoma, Kaposi'ssarcoma, sarcoma, or dermatofibrosarcoma protuberans, squamous cellcarcinoma, basal cell carcinoma, squamous cell carcinoma in situ(Bowen's disease), and melanoma.

In certain embodiments, the methods of treating skin diseases or skinconditions comprise administering a composition comprising one or morepicropodophyllin derivatives described by Vitale et al. (Journal ofOrganic Chemistry, 73:5795-5805, 2008), including the vinyl-lactones andaryltetralin lignan derivatives.

In certain embodiments, the method of treatment of skin diseases or skinconditions comprising administration of a composition comprisingpicropodophyllin derivatives described by Axelson and Bremberg (WO2013/132262 and WO 2013/132263); wherein the skin diseases or skinconditions is verruca (warts), common warts (verruca vulgaris), flatwarts (verruca plana), genital warts (condyloma accuminatum), certaintypes of ichthyosis, psoriasis, actinic keratosis, condyloma, molluscumcontagiosum, acanthosis nigricans, porokeratosis, seborrheic keratosis,fibroepithelial polyp (skin tag) or melasma.

In certain embodiments of the invention, skin diseases or skinconditions of the current invention include skin diseases or skinconditions other than cancer.

In certain embodiments of the invention, skin diseases or skinconditions of the current invention include skin diseases or skinconditions other than malignant hyperproliferative skin conditions.

In certain embodiments of the invention, skin diseases or skinconditions of the current invention includes one or plurality skindiseases or skin conditions selected from the group consisting ofverruca (warts), common warts (verruca vulgaris), flat warts (verrucaplana), genital warts (condyloma accuminatum), certain types ofichthyosis, psoriasis, actinic keratosis, condyloma, molluscumcontagiosum, acanthosis nigricans, porokeratosis, seborrheic keratosis,fibroepithelial polyp (skin tag), melasma, and malignanthyperproliferative skin conditions including angiosarcoma, Kaposi'ssarcoma, sarcoma, or dermatofibrosarcoma protuberans, squamous cellcarcinoma, basal cell carcinoma, squamous cell carcinoma in situ(Bowen's disease), and melanoma.

In some aspects, the current invention includes use of picropodophyllin,another compound described herein, and/or a pharmaceutically acceptableprecursor or prodrug thereof in preparation of a medicament fortreatment of skin diseases or skin conditions wherein wherein the skindiseases or skin conditions is verruca (warts), common warts (verrucavulgaris), flat warts (verruca plana), genital warts (condylomaaccuminatum), certain types of ichthyosis, psoriasis, actinic keratosis,condyloma, molluscum contagiosum, acanthosis nigricans, porokeratosis,seborrheic keratosis, fibroepithelial polyp (skin tag), melasma, andmalignant hyperproliferative skin conditions including angiosarcoma,Kaposi's sarcoma, sarcoma, or dermatofibrosarcoma protuberans, squamouscell carcinoma, basal cell carcinoma, squamous cell carcinoma in situ(Bowen's disease), or melanoma.

In certain embodiments, the medicament comprises one or morepicropodophyllin derivatives as described by Vitale et al., (Journal ofOrganic Chemistry, 73:5795-5805, 2008), including the vinyl-lactones andaryltetralin lignan derivatives.

In certain embodiments, the medicament comprises picropodophyllinderivatives described by Axelson and Bremberg (WO 2013/132262 and WO2013/132263); wherein the skin diseases or skin conditions is verruca(warts), common warts (verruca vulgaris), flat warts (verruca plana),genital warts (condyloma accuminatum), certain types of ichthyosis,psoriasis, actinic keratosis, condyloma, molluscum contagiosum,acanthosis nigricans, porokeratosis, seborrheic keratosis,fibroepithelial polyp (skin tag) or melasma.

In certain embodiments, the current invention includes use ofpicropodophyllin, another compound described herein, and/or apharmaceutically acceptable precursor or prodrug thereof in preparationof a medicament for treating skin diseases or skin conditions of thecurrent invention include skin diseases or skin conditions other thancancer.

Pharmaceutical Formulations, Doses, and Administration:

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in a conventional manner using one or morephysiologically acceptable carriers or excipients. For example, asolution can be prepared as in the Example provided below with a 100%propylene glycol solution. After dissolution in an appropriate vehicle,additional preparations could include a gel, cream, ointment, foam,aerosol, adhesive patch, spray, or powder. Although picropodophyllin isnearly completely insoluble in water, solutions for pharmacologic usecan be prepared by dissolving crystallized material in alcohol (such asethanol or isopropanol), chloroform, DMSO, (glacial) acetic acid, hotfatty oils, and ether.

Any suitable concentration of an active pharmaceutical ingredient may beused, where the active pharmaceutical ingredient is administered in aneffective amount to achieve its intended purpose. Determination of atherapeutically effective amount for a particular active ingredient iswell within the capability of persons skilled in the art.

The specific therapeutically effective dose level for any particularpatient will depend upon a variety of factors including activity of thespecific compound employed; the specific composition employed; the age,body weight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidentally with the specific compound employed; andlike factors well known in the medical arts.

The therapeutically effective dose of the pharmacologic agent can beadministered using any medically acceptable mode of administration.Although the skilled artisan would contemplate any of the modes ofadministration known to one of ordinary skill, preferably thepharmacologic agent is administered according to the recommended mode ofadministration, for example, the mode of administration listed on thepackage insert of a commercially available agent. In general, the dosemay comprise 0.01 mg to about 1 g/kg/day.

In general, the dose may depend on factors such as exact compound usedin the methods of the current invention, type of formulation used,indication being treated, severity of symptoms, mode of administration,age and sex of the subject etc. In some embodiments, a topicalformulation of the pharmacologic agent can be applied to any skin areain need of treatment, for example, a skin area of between 1 and 400 cm²,or any other area within the recited range, for example, 25, 50, 75,100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400 cm².

The pharmacologic compositions comprising picropodophyllin orderivatives thereof may contain from about 0.001% to about 10%picropodophyllin or a derivative (weight/volume), for example, fromabout 0.1 to 2.5%, 0.1 to 5%, 2.5 to 5.0%, 0.5 to 2.5%, or from about0.5 to 5% (weight/volume). In some embodiments, the concentrationpicropodophyllin or a derivative thereof may be about 0.1, 0.2, 0.3,0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7,1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1,3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5,4.6, 4.7, 4.8, 4.9, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 orabout 10.0% picropodophyllin or a derivative thereof (weight/volume), orany other dose within any recited range, or any range between any tworecited values.

For parenteral administration (e.g., subcutaneous, intramuscular,intravenous), the dose of picropodophyllin or a derivative thereof maybe about 0.05 mg/kg/day to about 20 mg/kg/day. For example, the dose maybe may be about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg,about 0.09 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg,about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg,about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg,about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1 mg,about 1.05 mg, about 1.1 mg, about 1.15 mg, about 1.2 mg, about 1.25 mg,about 1.3 mg, about 1.35 mg, about 1.4 mg, about 1.45 mg, about 1.5 mg,about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg,about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg,about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg,about, 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg,about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg,about, 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg,about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg,about, 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg,about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg,about, 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg,about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg,about 7.5 mg, about 8 mg, about 8.5 mg, about 8 mg, about 8.5 mg, about10 mg, about 10.5 mg, about 11 mg, about 12 mg, about 13 mg, about 14mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg,about 20 mg or any other dose within the recited range, or any rangebetween any two recited doses. A patient may receive this dose as asingle bolus or infusion over 1, 2, 3, 4-6, 6-10 hours, once, twice,thrice, or 4-6 times a day. The treatment may be continued from anywherebetween one day and two years.

For oral administration, the dose may be about 0.5 mg/day to about 10000mg/day. For example, the dose may be may be about 0.5 mg, about 0.6 mg,about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg,about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg,about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg,about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 30 mg,about 35 mg, about 40 mg, about 45 mg, 50 mg, about 55 mg, about 60 mg,about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about100 mg, about 105 mg, about 110 mg, about 120 mg, about 130 mg, about140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about490 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg,about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg,about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about4700 mg, about 4800 mg, about 4900 mg, about 5000 mg, about 5100 mg,about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg,about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg,about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg,about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800mg, about 9900 mg, about 10000 mg, or any other dose within the recitedrange. A patient may receive this dose as a tablet, capsule, or othersuitable oral administration form, once, twice, thrice, or 4-6 times aday. The treatment may be continued from anywhere between one day andtwo years.

The compounds described herein may be administered directly, they mayalso be formulated to include at least one pharmaceutical acceptablecarriers, diluents, excipients, adjuvants, fillers, buffers,preservatives, lubricants, solubilizers, surfactants, wetting agents,masking agents, coloring agents, flavoring agents, and sweeteningagents. Also, as described herein, such formulation may also includeother active agents, for example, other therapeutic or prophylacticagents.

Methods of making a pharmaceutical composition include admixing at leastone active compound, as defined above, together with one or more otherpharmaceutically acceptable ingredients, such as carriers, diluents,excipients, and the like. When formulated as discrete units, such astablets or capsules, each unit contains a predetermined amount of theactive compound.

An acceptable carrier refers to those carriers that cause at most,little to no irritation, provide suitable preservation if needed, anddeliver picropodophyllin and/or one or more of its metabolites, analogsor precursors of the present invention in a homogenous dosage.Pharmaceutically acceptable carriers can include any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents, and the like that arephysiologically compatible, sterile aqueous solutions or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersion. The use of such media and agents forpharmaceutically active substances is well known in the art.Supplementary active compounds can also be incorporated into thecompositions.

For pulmonary delivery, picropodophyllin and/or one or more of itsmetabolites, analogs or precursors may be combined with pulmonaryacceptable preservatives, co-solvents, surfactants, viscosity enhancers,penetration enhancers, buffers, sodium chloride, or water to form anaqueous, sterile suspension or solution.

The formulations may be prepared by any methods well known in the art ofpharmacy. The formulation may be prepared to provide for rapid or slowrelease; immediate, delayed, timed, or sustained release; or acombination thereof. Formulations may be in the form of liquids,solutions, suspensions, emulsions, elixirs, syrups, electuaries,mouthwashes, drops, tablets, granules, powders, lozenges, pastilles,capsules, gels, pastes, ointments, creams, lotions, oils, foams, sprays,mists, or aerosols. Formulations may be provided as a patch, adhesiveplaster, bandage, dressing, or in the form of depot or reservoir. Manymethods for the preparation of such formulations are known to thoseskilled in the art.

Routes of Administration:

In certain embodiments, pharmaceutical compositions of the presentinvention may be formulated for administration by any route ofadministration, including but not limited to systemic, peripheral, ortopical. Illustrative routes of administration include, but are notlimited to, oral, such as by ingestion, buccal, sublingual, transdermalincluding, such as by a patch, plaster, and the like, transmucosalincluding, such as by a patch, plaster, and the like, intranasal, suchas by nasal spray, ocular, such as by eye drops, pulmonary, such as byinhalation or insufflation therapy using, such as via an aerosol throughthe mouth or nose, rectal, such as by suppository or enema, vaginal,such as by pessary, parenteral, such as by injection, includingsubcutaneous, intradermal, intramuscular, intravenous, intraarterial,intracardiac, intrathecal, intraspinal, intracapsular, subcapsular,intraorbital, intraperitoneal, intratracheal, subcuticular,intraarticular, subarachnoid, and by implant of a depot or reservoir,such as intramuscularly, topical including, such as by cream, gel,ointment, lotion, solution and the like. Methods of preparingpharmaceutical formulations are well known in the art. Dosage of thepharmaceutical compositions may vary by route of administration. Certainadministration methods may include the step of administering thecomposition one or more times a day to obtain the desired therapeuticeffect.

Picropodophyllin and/or its derivatives can be formulated for oraldelivery as a solution, gelatin capsule, or tablet. The oral liquidformulations and capsule formulations are well known to one of ordinaryskill in the art. The tablet formulation can include: 1-80%picropodophyllin or a derivative thereof; 10-90% fillers, disintegrants,lubricants, glidants, binders; and 1-20% additional compounds thatensure easy disintegration, disaggregation, and dissolution of thetablet in the stomach or the intestine.

The tablet may be formulated for immediate release, sustained release,or delayed or modified release. The tablet may be optionally coated canmake the tablet resistant to the stomach acids and it disintegrates inthe duodenum, jejunum and colon as a result of enzyme action or alkalinepH. These formulations are well known to one of ordinary skill in theart. The tablets may be further coated with sugar, varnish, or wax tomask the taste.

An exemplary tablet formulation contains: 5-50% picropodophyllin; acids,bases or salts thereof such as citric acid and sodium citrate; a solventlike glycerin or propylene glycol, alcohol, or water; one or more ofpolyethylene glycol, polyvinylpyrrolidone, dextran, polyacrylic acid,polyethylene oxide, starches, cellulose or modified cellulose (such asmethylcellulose, carboxymethyl cellulose, hydroxymethyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, microcrystallinecellulose, hydroxypropyl cellulose), sucrose, lactose, xylitol, sorbitolor maltitol; and pharmaceutically acceptable gelatin or modifiedgelatin.

Alternatively, picropodophyllin or its derivatives may be formulated forparenteral delivery by a route such as intravenous, subcutaneous,intramuscular, and intra-articular administration. These formulationsare either liquids or lyophilizates. The liquid or lyophilizedformulations comprise of 1-50% picropodophyllin or its derivatives andremaining ingredients selected from solubilizers, stabilizers, buffers,tonicity modifiers, bulking agents, viscosity enhancers/reducers,surfactants, chelating agents, and adjuvants. These ingredients are wellknown to one of ordinary skill in the art. Lyophilized formulations needto be reconstituted prior to administration. Liquid formulations areoptionally diluted with pharmaceutically acceptable diluents such as 5%Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP. Theseformulations are preferably administered by infusion although bolusadministration is also possible.

An exemplary formulation comprises: picropodophyllin or its derivatives;one or more of sodium citrate, polyvinylpyrrolidone andhydroxypropylcellulose and polyethylene glycol, methylcellulse,propylene glycol, peanut oil, benzyl alcohol, N,N-dimethylacetamide,polyoxyethylated castor oil, dehydrated alcohol, and water.

Alternatively, picropodophyllin or its derivatives may be formulated fortopical delivery in the form of a collodion, cream, emulsion, foam, gel,lotion, ointment, paste, solution, or powder. These formulations arewell known to one of ordinary skill in the art.

An exemplary formulation comprises: picropodophyllin or a derivativethereof; one or more of benzoine tincture, benzoine Sumatra tincture,hard paraffin, soft paraffin, microcrystalline wax, ceresine, wool fat,beeswax, emulsifying wax, cetrimide, N,N-dimethylacetamide, benzylalcohol, polyvinylpyrrolidone, hydroxypropylcellulose, polyethyleneglycol, methylcellulse, propylene glycol, olive oil, coconut oil, sesameoil, almond oil peanut oil, polyoxyethylated castor oil, dehydratedalcohol, and hydrocarbon bases including but not limited to whitepetrolatum, water.

In certain embodiments, picropodophyllin or a derivative thereof may beadministered in form of a hydrogel. Gels are solid or semi-solid inappearance and still contain a high concentration of water. The gels maycontain picropodophyllin or a derivative thereof or entrap granulescontaining them. The gels may optionally comprise of one or more ofadditional solvents, solutes, solubilizers, stabilizers, buffers,bulking agents, surfactants. The gels may contain additional drugs thatreduce or prevent itching, swelling, pain, redness, and inflammation.They can optionally be configured for a slow or delayed release. Thecompounds described herein can be formulated in a hydrogel, and thathydrogel that may further include an additional protective film that isfully or partially air- and water-proof or air- and water-repellent andan adhesive surface that can be positioned, for example, around theperiphery of the skin lesion that being treated. The methods of makinghydrogels are well known in the art.

In some embodiments, compositions comprising picropodophyllin or aderivative thereof can be co-administered with other compounds ormedications to either enhance its therapeutic effect or to minimizepossible adverse effects. To increase its therapeutic effect it can becombined with a cytoxic agent, for example, fluorouracil or ingenolmebutate; a desquamating agent such as retinoic acid, an alpha hydroxylacid (i.e., glycolic acid), or a beta hydroxyl acid (i.e., salicylicacid); or an immune stimulating compound such as imiquimod. To minimizeadverse reactions such as inflammation, burning, and erythemapicropodophyllin or a derivative thereof can be co-administered with asteroidal anti-inflammatory compound such as triamcinolone orhydrocortisone; a non-steroidal anti-inflammatory drug (NSAID) such asdiclofenac sodium; a topical immunomodulator such as pimecrolimus; or ananti-pruritic agent such as pramoxine or menthol.

In certain further embodiments, modes of administration can includetablets, pills, capsules, injectables, topical application and aerosolall of which are capable of formulation by one of ordinary skill in theart.

In another embodiment, a method is provided for administering atherapeutically effective amount of picropodophyllin or one of itsmetabolites, analogs or precursors to treat one or more of the followingskin or medical conditions: verruca (warts), actinic keratosis,condyloma, molluscum contagiosum, squamous cell carcinoma, basal cellcarcinoma, squamous cell carcinoma in situ, melanoma, acanthosisnigricans, porokeratosis, seborrheic keratosis, fibroepithelial polyp(skin tag), melasma, angiosarcoma, Kaposi's sarcoma, sarcoma, acne(e.g., vulgaris, comedonal acne vulgaris, or cystic acne vulgaris) andconditions related thereto (e.g., scarring), perioral dermatitis,trichoepithelliomas and related genetic syndromes that cause multipletrichoepitheliomas. and dermatofibrosarcoma protuberans in a patient.

Examples

To date, 56 patients have been studied to determine the efficacy ofpicropodophyllin in treating actinic keratoses. The patients wererandomized into four groups, and the patients in each group were treatedwith a solution containing either 0.5%, 1.25%, or 2.0% picropodophyllin(w/v) in propylene glycol, or a placebo constituting only the vehiclepropylene glycol. The picropodophyllin solution was prepared in 100%propylene glycol solution. The solutions were prepared asepticallyfollowing GMP protocols. The affected areas of the body variouslyincluded the scalp, face, arms, and legs. Without knowing which one ofthe four solutions they were applying, the subjects self-applied one ofthe solutions to the skin. After initial application, the subjectsgently massaged the solutions into their skin. This was done twice dailyfor 1 week. Lesions (actinic keratosis) were palpated and visualized bya trained lesion counter who is a board certified dermatologist. Thesame investigator evaluated each subject at each visit for consistency.The subjects were evaluated at baseline, day 3, day 7, day 14, day 28,day 56 and day 90. The results are shown in the Table below. Within thetreatment area, the number of lesions were counted, regardless of theirsize. The change in the number of lesions (% decline from baseline)within the treatment area was calculated and the results are shown inthe table below:

TABLE I # of Patients % Decline Completed to Date from Baseline 28 56 9028 56 90 [PPP] w/v # Patients days days days days days days 0.50% 4 4 33 −56^(AB) −82^(AB) −90^(AB) 1.25% 23 13 10 5 −53^(AB) −73^(AB) −65^(AB)2.00% 9 8 7 5 −17  −55^(AB) −84^(AB) Placebo 20 18 16 14 −12  −13 −19^(B)  ^(A)Indicates value is significantly different (p-value < 0.05)from Placebo ^(B)Indicates value is significantly different (p-value <0.05) from BaselineThese results showed that compared to placebo, all the doses showedsignificant reduction in the number of lesions in the treatment area, asnoted in Table I.

What is claimed is:
 1. A method of reducing the number of actinickeratosis lesions in a patient in need thereof, the method comprisingadministering, to the patient, a composition comprising atherapeutically effective amount of picropodophyllin.
 2. The method ofclaim 1, wherein the composition is formulated for topicaladministration to the patient's skin.
 3. The method of claim 1, whereinthe composition is formulated for administration by one or more of thefollowing routes: oral, subcutaneous, intravenous, intramuscular, andnasal inhalation.
 4. The method of claim 1, wherein the compositioncomprising a therapeutically effective amount of picropodophyllincontains from about 0.1 to 5% (weight/volume) of picropodophyllin. 5.The method of claim 4, wherein the composition contains from about 0.5to 2.5% (weight/volume) of picropodophyllin.
 6. The method of claim 5,wherein the composition contains from about 0.5 to 2.0% (weight/volume)of picropodophyllin.
 7. The method of claim 1, wherein the compositionfurther comprises a solvent selected from: ethanol, isopropanol,chloroform, DMSO, glacial acetic acid, hot fatty oils, and ether, andcombinations thereof.
 8. The method of claim 1, wherein the compositioncomprising a therapeutically effective amount of picropodophyllinfurther comprises an ingredient selected from: benzoine tincture, hardparaffin, soft paraffin, microcrystalline wax, ceresine, wool fat,beeswax, emulsifying wax, cetrimide, N,N-dimethylacetamide, benzylalcohol, polyvinylpyrrolidone, hydroxypropylcellulose, polyethyleneglycol, methylcellulose, propylene glycol, olive oil, coconut oil,sesame oil, almond oil, peanut oil, polyoxyethylated castor oil,dehydrated alcohol, white petrolatum, water, and combinations thereof.